ABSTRACT As the Zika virus (ZIKV) epidemic sweeps through the Americas, the risks to public health are tremendous. Although prospective studies are limited, microcephaly and other major fetal abnormalities may occur in up to 30% of children born to ZIKV-infected mothers. There is a pressing need for new diagnostic, prognostic, and therapeutic tools to combat this global health threat. We propose that the maternal immune response may provide a window into understanding the pathogenesis of ZIKV during pregnancy. We therefore aim to define the transcriptional signatures of the immune response to ZIKV during pregnancy and to identify signatures predictive of adverse fetal outcomes. Defining these signatures could have a significant impact on the management of pregnant women exposed to ZIKV by serving as a basis for improved diagnostic tests for detecting ZIKV, therapeutic approaches targeting identified pathways, and an improved ability to predict fetal risk.